Characterization of pancreatic NMDA receptors as possible drug targets for diabetes treatment.

Abstract:

:In the nervous system, NMDA receptors (NMDARs) participate in neurotransmission and modulate the viability of neurons. In contrast, little is known about the role of NMDARs in pancreatic islets and the insulin-secreting beta cells whose functional impairment contributes to diabetes mellitus. Here we found that inhibition of NMDARs in mouse and human islets enhanced their glucose-stimulated insulin secretion (GSIS) and survival of islet cells. Further, NMDAR inhibition prolonged the amount of time that glucose-stimulated beta cells spent in a depolarized state with high cytosolic Ca(2+) concentrations. We also noticed that, in vivo, the NMDAR antagonist dextromethorphan (DXM) enhanced glucose tolerance in mice, and that in vitro dextrorphan, the main metabolite of DXM, amplified the stimulatory effect of exendin-4 on GSIS. In a mouse model of type 2 diabetes mellitus (T2DM), long-term treatment with DXM improved islet insulin content, islet cell mass and blood glucose control. Further, in a small clinical trial we found that individuals with T2DM treated with DXM showed enhanced serum insulin concentrations and glucose tolerance. Our data highlight the possibility that antagonists of NMDARs may provide a useful adjunct treatment for diabetes.

journal_name

Nat Med

journal_title

Nature medicine

authors

Marquard J,Otter S,Welters A,Stirban A,Fischer A,Eglinger J,Herebian D,Kletke O,Klemen MS,Stožer A,Wnendt S,Piemonti L,Köhler M,Ferrer J,Thorens B,Schliess F,Rupnik MS,Heise T,Berggren PO,Klöcker N,Meissner T,Ma

doi

10.1038/nm.3822

subject

Has Abstract

pub_date

2015-04-01 00:00:00

pages

363-72

issue

4

eissn

1078-8956

issn

1546-170X

pii

nm.3822

journal_volume

21

pub_type

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